Drug hypersensitivity syndrome (DRESS)

At a glance

• A delayed, T-cell-mediated (type IVb) drug reaction with fever, widespread rash, facial oedema, lymphadenopathy, eosinophilia or atypical lymphocytes, and internal organ involvement. Japan calls it drug-induced hypersensitivity syndrome (DiHS).
• Incidence is about 2 to 5 per million per year, and mortality about 2 to 10%, higher with myocarditis and in older patients on allopurinol.
• Latency is long: 2 to 8 weeks after starting the drug. The drug started yesterday is usually innocent.
• It keeps getting worse after the drug is stopped, relapses with fast steroid tapers and herpesvirus reactivation, and can leave autoimmune disease months later.
• Treatment depends on severity: very high potency topical steroid for mild disease, systemic glucocorticoid with a slow taper for severe disease.
• For the broader approach to drug rashes, see cutaneous drug reactions and drug allergy.

Causes

Drug class	Examples	Notes
Xanthine oxidase inhibitor	Allopurinol	Commonest cause in many series. Risk with CKD, high starting dose, thiazides, HLA-B*58:01
Aromatic anticonvulsants	Carbamazepine, phenytoin, phenobarbital, lamotrigine, oxcarbazepine	Cross-react. HLA-A*31:01 for carbamazepine. Lamotrigine risk rises with fast titration and valproate
Antibiotics	Vancomycin, sulfonamides (co-trimoxazole), minocycline, beta-lactams, anti-tuberculosis drugs	Vancomycin DRESS typically arrives 2 to 4 weeks into long courses for bone, joint or line infection (HLA-A*32:01)
Sulfones and sulfonamides	Dapsone, sulfasalazine	HLA-B*13:01 for dapsone
Antiretrovirals	Nevirapine, raltegravir	Abacavir hypersensitivity is a separate syndrome (HLA-B*57:01)
Others	Strontium ranelate, mexiletine, NSAIDs (rare), some kinase inhibitors

Minocycline DRESS often involves the lungs and heart and can be followed by autoimmune thyroid disease.

Pathophysiology

• The drug (or its metabolite) is presented on particular HLA molecules to T cells. Th2 cytokines, especially IL-5, drive eosinophilia.
• Herpesvirus reactivation follows a typical sequence: HHV-6, then EBV, HHV-7 and CMV. Virus-specific T cells cross-react with drug-specific responses and keep the inflammation going.
• Early expansion of regulatory T cells limits the acute phase. Their later loss may explain post-DRESS autoimmunity.

Recognition

• Fever (often the first sign, 38.5 °C or more) and malaise, then a morbilliform rash that becomes confluent and infiltrated, often covering over 50% of the body. It may turn erythrodermic, purpuric or show small pustules and targetoid lesions.
• Facial oedema, especially of the midface and eyelids. This is a strong clue.
• Lymphadenopathy at 2 or more sites.
• Mucosal involvement is mild if present (cheilitis, a few oral erosions). Extensive mucosal erosions and skin detachment point to SJS/TEN.

Organ involvement

Organ	Frequency and features
Liver	The commonest, in most patients. Cholestatic or mixed more than hepatocellular. Acute liver failure is the main cause of death in many series
Kidney	Acute interstitial nephritis, especially with allopurinol and in older people with CKD
Lung	Interstitial pneumonitis, effusions, ARDS. Associated with minocycline
Heart	Eosinophilic myocarditis, sometimes weeks after onset, occasionally fulminant and necrotising. Highest mortality
Others	Pancreatitis, colitis, encephalitis, thyroiditis, haemophagocytic lymphohistiocytosis (HLH)

Blood

• Eosinophilia, often over 1.5 × 10⁹/L. It can lag the rash by several days, so repeat the count.
• Atypical lymphocytes, lymphocytosis or lymphopenia, thrombocytopenia.

Pitfall: a normal first eosinophil count doesn't exclude DRESS. Fever, rash, facial oedema and hepatitis weeks into a new drug is enough to act.

Diagnosis: RegiSCAR

Item	Score
Fever 38.5 °C or more	No or unknown: −1
Enlarged lymph nodes (2 or more sites, over 1 cm)	+1
Eosinophilia 0.7 to 1.49 × 10⁹/L / 1.5 or more	+1 / +2
Atypical lymphocytes	+1
Rash over 50% body surface area	+1
Rash suggestive (2 of: facial oedema, infiltration, purpura, scaling)	+1 (no: −1)
Biopsy suggesting another diagnosis	−1
Organ involvement: 1 / 2 or more	+1 / +2
Resolution in 15 days or more	No or unknown: −1
Three or more tests excluding other causes negative (ANA, blood cultures, hepatitis A, B, C serology, chlamydia or mycoplasma)	+1

6 or more definite, 4 to 5 probable, 2 to 3 possible, under 2 no case. The Japanese DiHS criteria also require HHV-6 reactivation for typical DiHS.

Investigations

The 2024 international Delphi consensus (JAMA Dermatology) set a baseline work-up for all suspected cases, with organ-specific tests added as needed. Items marked local practice are common but weren't consensus statements.

• FBC with differential and film, LFTs, urea, creatinine and electrolytes, urinalysis and urine protein-creatinine ratio, lipase, CRP.
• ECG in everyone. Troponin and BNP or proBNP if cardiac involvement is suspected, then echocardiogram or cardiac MRI. Many units also check troponin at baseline (local practice; universal troponin didn't reach consensus).
• TSH at baseline (and later).
• HHV-6, EBV and CMV viral load in blood in all suspected cases, repeated with clinical change. HHV-7 is optional.
• Skin biopsy: interface dermatitis, spongiosis, dermal eosinophils and atypical lymphocytes. It mainly excludes SJS/TEN, lymphoma and vasculitis.
• Hepatitis A, B and C serology if the liver is involved, and hepatitis B and C before systemic treatment.
• Exclude other mimics as the picture suggests: blood cultures, ANA, mycoplasma. The consensus advised against routine HIV screening; test selectively on risk.
• Chest imaging and lung function if respiratory symptoms.
• Ferritin, triglycerides and fibrinogen if HLH is a concern (persisting fever, cytopenias, splenomegaly).

Differential diagnosis

• SJS/TEN, AGEP (pustules within days, neutrophilia), viral exanthem (EBV, acute HIV), serum sickness-like reaction.
• Hypereosinophilic syndrome, eosinophilic granulomatosis with polyangiitis.
• Angioimmunoblastic T-cell lymphoma and other lymphomas (fever, rash, nodes, eosinophilia).
• Adult-onset Still disease, sepsis, HLH.

Management

Drugs

• Stop the culprit immediately, and every non-essential drug started in the previous 8 weeks.
• Avoid adding new drugs where possible. Patients with active DRESS react more readily to unrelated drugs (multiple drug hypersensitivity).
• Substitutes: levetiracetam or valproate for aromatic anticonvulsants; febuxostat is generally avoided during active DRESS and only considered later with specialist input; a non-glycopeptide (such as daptomycin, chosen with ID) for vancomycin.

Treatment by severity (Delphi 2024)

The consensus grades severity as mild, moderate or severe by the degree of liver, kidney and blood involvement and damage to other organs.

Severity	Treatment	Taper
Mild	Very high potency topical steroid (clobetasol 0.05%) to the whole skin	Over 6 weeks to 3 months
Moderate	Very high potency topical steroid or systemic glucocorticoid	Over 6 weeks to 3 months
Severe	Systemic glucocorticoid in all. The consensus gives no doses; expert practice is prednisolone 0.5 to 1 mg/kg/day, with IV methylprednisolone pulses for life-threatening disease	Over 3 to 6 months

• The risk of a short taper is relapse, seen in about 10 to 15% of patients.
• Steroid-refractory DRESS: ciclosporin, anti-IL-5 or anti-IL-5 receptor antibodies (mepolizumab, benralizumab), or IVIG (toxicity is reported when given without steroids, so combine them). JAK inhibitors have case reports. Evidence for all is from case series.
• High CMV viral load: consider ganciclovir or valganciclovir.
• Supportive care: emollients, fluid balance, nutrition, ICU for organ failure. Transplant hepatology for acute liver failure. Treat myocarditis with high-dose steroids and cardiology input.

Follow-up

• Review within the first month of discharge and regularly for 6 months.
• Repeat blood tests guided by the organs involved.
• Late autoimmunity (months to years): autoimmune thyroiditis (the commonest), type 1 diabetes (can be fulminant, with ketoacidosis), autoimmune hepatitis, lupus, alopecia areata, autoimmune haemolytic anaemia. Check TSH and glucose during convalescence and with any new symptoms.
• Screen for steroid adverse effects with long tapers (glucose, bone protection, PJP prophylaxis if prolonged high dose).
• Offer psychological support.

Allergy work-up and labelling

• Never re-challenge, and no desensitisation. ASCIA considers drug challenge contraindicated after a severe cutaneous adverse reaction.
• Patch testing at least 6 months after recovery helps identify the culprit when several drugs are possible. It's most useful for anticonvulsants and beta-lactams, and a negative result doesn't exclude a drug. Delayed-reading intradermal tests are used with caution by specialists. Skin prick testing has no role.
• Document the drug, the reaction (DRESS, with date) and cross-reactive drugs to avoid. Report to the TGA and record in My Health Record. A medical alert bracelet is reasonable.
• First-degree relatives may share HLA risk alleles. Mention this when the culprit has a known HLA association.

Prevention

• HLA-B*58:01 testing before allopurinol in Han Chinese, Korean and Thai ancestry. Start low (50 to 100 mg daily, 50 mg in CKD) and titrate. See gout.
• HLA-B*15:02 and HLA-A*31:01 before carbamazepine in the relevant ancestries. See epilepsy.
• Slow lamotrigine titration, halved when combined with valproate.
• Monitor FBC, LFTs and creatinine weekly on long vancomycin courses, which also catches DRESS early.

Special populations

• Older people with CKD on allopurinol have the highest mortality. The combination with a thiazide adds risk.
• HIV: higher rates of drug hypersensitivity, including nevirapine and co-trimoxazole DRESS.
• Pregnancy: data are limited. Systemic steroids are acceptable, and mother and fetus are monitored jointly with obstetric medicine.
• Aboriginal and Torres Strait Islander people have high rates of gout and CKD, so allopurinol dosing and monitoring matter.

Pitfalls

• Blaming the antibiotic started 2 days ago while the allopurinol started 5 weeks ago continues.
• Calling it a viral rash because HHV-6 or EBV PCR is positive. Reactivation is part of DRESS.
• Treating fever and rash weeks into vancomycin as treatment failure and escalating antibiotics.
• Tapering prednisolone over 2 weeks and seeing the rash, eosinophilia and hepatitis return.
• Not checking troponin, then missing late myocarditis.
• Discharging without planning thyroid and glucose checks over the following months.
• Swapping carbamazepine for phenytoin, oxcarbazepine or lamotrigine.